To date, many cancers are still areas of unmet medical needs, and accordingly, means to more effectively treat cancer, and to treat cancer in a broader range of cancers are needed.
In addition to the suffering caused by the cancer itself, many patients suffer from cancer cachexia, a medical condition triggered by the cancer that typically involves weight loss and loss of skeletal muscle mass. Cancer cachexia accounts for more than 20 percent of all cancer-related deaths (Murphy K T and Lynch G S: Update on emerging drugs for cancer cachexia. Expert Opin Emerg Drugs. 2009 December; 14(4):619-32.).
Thus, in order to improve the treatment and prognosis of cancers which lead to cancer cachexia, treatment regimens that target both of these medical conditions are needed. To date, most of the emerging drugs for treatments of cancer cachexia are drugs that target cachexia but not the cancer itself (see Murphy K T and Lynch G S: Update on emerging drugs for cancer cachexia. Expert Opin Emerg Drugs. 2009 December; 14(4):619-32.). Only very few drugs are effective against both the cancer and cancer cachexia, and therefore, complex treatment regimens that combine anti-cancer drugs and anti-cancer cachexia drugs are often times needed. Accordingly, there is still an unmet medical need for drugs that can be used to effectively treat both cancer and cancer cachexia in a broad range of cancers.
Many types of cancer are known to express growth factors, including factors such as VEGF, PDGF, TGF-β and GDF-15.
GDF-15, growth and differentiation factor-15, is a divergent member of the TGF-β superfamily. It is a protein which is intracellularly expressed as a precursor, subsequently processed and eventually becomes secreted from the cell into the environment. Both the active, fully processed (mature) form and the precursor of GDF-15 can be found outside cells. The precursor covalently binds via its COOH-terminal amino acid sequence to the extracellular matrix (Bauskin A R et al., Cancer Research 2005) and thus resides on the exterior of a cell. The active, fully processed (mature) form of GDF-15 is soluble and is found in blood sera. Thus, the processed form of GDF-15 may potentially act on any target cell within the body that is connected to the blood circulation, provided that the potential target cell expresses a receptor for the soluble GDF-15 ligand.
During pregnancy, GDF-15 is found under physiological conditions in the placenta. However, many malignant cancers (especially aggressive brain cancers, melanoma, lung cancer, gastrointestinal tumors, colon cancer, pancreatic cancer, prostate cancer and breast cancer (Mimeault M and Batra S K, J. Cell Physiol 2010)) exhibit increased GDF-15 levels in the tumor as well as in blood serum. Likewise, correlations have been described between high GDF-15 expression and chemoresistance (Huang C Y et al., Clin. Cancer Res. 2009) and between high GDF-15 expression and poor prognosis, respectively (Brown D A et al., Clin. Cancer Res. 2009).
GDF-15 is expressed in gliomas of different WHO grades as assessed by immunohistochemistry (Roth et al., Clin. Cancer Res. 2010). Further, Roth et al. stably expressed short hairpin. RNA-expressing DNA constructs targeting endogenous GDF-15 or control constructs in SMA560 glioma cells. When using these pre-established stable cell lines, they observed that tumor formation in mice bearing GDF-15 knockdown SMA560 cells was delayed compared to mice bearing control constructs.
Patent application PCT/EP2013/070127 relates to monoclonal anti-GDF-15 antibodies, in particular to an antibody produced by the hybridoma cell line B1-23 deposited with the Deutsche Sammlung für Mikroorganismen und Zellkulturen GmbH (DSMZ) under the accession No. DSM ACC3142 under the Budapest treaty. PCT/EP2013/070127 also relates to uses of the anti-GDF-15 antibodies.
Patent applications WO 2005/099746 and WO 2009/021293 relate to an anti-human-GDF-15 antibody (Mab26) capable of antagonizing effects of human GDF-15 on tumor-induced weight loss in vivo in mice: In these documents, immunologically compromised mice were administered with human tumor cells (prostate carcinoma cells DU145) transfected with plasmids overexpressing human GDF-15. Tumor cells carrying plasmids lacking a GDF-15 sequence served as a negative control. Those mice expressing xenograft GDF-15 exhibited a tumor-induced weight loss (clinical term: cachexia) and anorexia. A single intraperitoneal administration of 1 mg of Mab26 from WO 2005/099746 resulted in a complete reversal of tumor-induced weight loss. WO 2005/099746 and WO 2009/021293 do not disclose effects of an anti-human-GDF-15 antibody on tumor growth. Moreover, these documents are silent as to whether anti-human-GDF-15 antibodies could lead to an increase in body weight of the treated mice compared to their body weight before the onset of cachexia.
Similarly, Johnen H et al. (Nature Medicine, 2007) reported effects of an anti-human-GDF-15 monoclonal antibody on cancer-induced anorexia and weight loss but did not observe any effects of the anti-human-GDF-15 antibody on the size of the tumor formed by the cancer, even when the antibody was administered at a high dosage of 1 mg, and thus the antibody did not inhibit growth of the cancer.
Accordingly, to date, there was still a need in the art for means to effectively treat cancer and cancer cachexia, and for means to treat cancer and cancer cachexia in a broader range of cancers.
It is therefore an object of the invention to obtain means that can be used to effectively treat cancer cachexia, and to also effectively treat cancer, and means that can be used to treat cancer cachexia, and to also effectively treat cancer in a broader range of cancers.
In an effort to find means to achieve these objects, the present inventors have surprisingly found that a monoclonal antibody to human GDF-15 can be used to treat cancer cachexia and to also treat cancer of human xenograft tumors in mice.
Additionally, an antibody to human GDF-15 in accordance with the present invention has an equilibrium dissociation constant of about 790 pM for recombinant GDF-15 even without additional affinity maturation, which is a higher affinity compared to most known therapeutic antibodies.
Thus, the antibody to human GDF-15 according to the present invention has superior properties compared to antibodies known from the art, and is particularly useful for inhibiting cancer growth and cancer cachexia. The antibody of the present invention is therefore useful for treating cancer and for treating cancer cachexia. Accordingly, the present invention was completed.